Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity

The DNA binding domains of Androgen/Glucocorticoid receptors (AR/GR), members of class I steroid receptors, bind as a homo-dimer to a cis-regulatory element. These response elements are arranged as inverted repeat (IR) of hexamer “AGAACA”, separated with a 3 base pairs spacer. DNA binding domains of...

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Main Authors: Mahdi Bagherpoor Helabad, Senta Volkenandt, Petra Imhof
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-01-01
Series:Frontiers in Molecular Biosciences
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fmolb.2020.00004/full
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spelling doaj-42d3513610fe405aa88d366f9ddf8fbc2020-11-25T01:15:45ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-01-01710.3389/fmolb.2020.00004502452Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding SpecificityMahdi Bagherpoor HelabadSenta VolkenandtPetra ImhofThe DNA binding domains of Androgen/Glucocorticoid receptors (AR/GR), members of class I steroid receptors, bind as a homo-dimer to a cis-regulatory element. These response elements are arranged as inverted repeat (IR) of hexamer “AGAACA”, separated with a 3 base pairs spacer. DNA binding domains of the Androgen receptor, AR-DBDs, in addition, selectively recognize a direct-like repeat (DR) arrangement of this hexamer. A chimeric AR protein, termed SPARKI, in which the second zinc-binding motif of AR is swapped with that of GR, however, fails to recognize DR-like elements. By molecular dynamic simulations, we identify how the DNA binding domains of the wild type AR/GR, and also the chimeric SPARKI model, distinctly interact with both IR and DR response elements. AR binds more strongly to DR than GR binds to IR elements. A SPARKI model built from the structure of the AR (SPARKI-AR) shows significantly fewer hydrogen bond interactions in complex with a DR sequence than with an IR sequence. Moreover, a SPARKI model based on the structure of the GR (SPARKI-GR) shows a considerable distortion in its dimerization domain when complexed to a DR-DNA whereas it remains in a stable conformation in a complex with an IR-DNA. The diminished interaction of SPARKI-AR with and the instability of SPARKI-GR on DR response elements agree with SPARKI's lack of affinity for these sequences. The more GR-like binding specificity of the chimeric SPARKI protein is further emphasized by both SPARKI models binding even more strongly to IR elements than observed for the DNA binding domain of the GR.https://www.frontiersin.org/article/10.3389/fmolb.2020.00004/fullandrogen receptorglucocorticoid receptorresponse elementprotein-DNA interactionchimeric SPARKI protein
collection DOAJ
language English
format Article
sources DOAJ
author Mahdi Bagherpoor Helabad
Senta Volkenandt
Petra Imhof
spellingShingle Mahdi Bagherpoor Helabad
Senta Volkenandt
Petra Imhof
Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity
Frontiers in Molecular Biosciences
androgen receptor
glucocorticoid receptor
response element
protein-DNA interaction
chimeric SPARKI protein
author_facet Mahdi Bagherpoor Helabad
Senta Volkenandt
Petra Imhof
author_sort Mahdi Bagherpoor Helabad
title Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity
title_short Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity
title_full Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity
title_fullStr Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity
title_full_unstemmed Molecular Dynamics Simulations of a Chimeric Androgen Receptor Protein (SPARKI) Confirm the Importance of the Dimerization Domain on DNA Binding Specificity
title_sort molecular dynamics simulations of a chimeric androgen receptor protein (sparki) confirm the importance of the dimerization domain on dna binding specificity
publisher Frontiers Media S.A.
series Frontiers in Molecular Biosciences
issn 2296-889X
publishDate 2020-01-01
description The DNA binding domains of Androgen/Glucocorticoid receptors (AR/GR), members of class I steroid receptors, bind as a homo-dimer to a cis-regulatory element. These response elements are arranged as inverted repeat (IR) of hexamer “AGAACA”, separated with a 3 base pairs spacer. DNA binding domains of the Androgen receptor, AR-DBDs, in addition, selectively recognize a direct-like repeat (DR) arrangement of this hexamer. A chimeric AR protein, termed SPARKI, in which the second zinc-binding motif of AR is swapped with that of GR, however, fails to recognize DR-like elements. By molecular dynamic simulations, we identify how the DNA binding domains of the wild type AR/GR, and also the chimeric SPARKI model, distinctly interact with both IR and DR response elements. AR binds more strongly to DR than GR binds to IR elements. A SPARKI model built from the structure of the AR (SPARKI-AR) shows significantly fewer hydrogen bond interactions in complex with a DR sequence than with an IR sequence. Moreover, a SPARKI model based on the structure of the GR (SPARKI-GR) shows a considerable distortion in its dimerization domain when complexed to a DR-DNA whereas it remains in a stable conformation in a complex with an IR-DNA. The diminished interaction of SPARKI-AR with and the instability of SPARKI-GR on DR response elements agree with SPARKI's lack of affinity for these sequences. The more GR-like binding specificity of the chimeric SPARKI protein is further emphasized by both SPARKI models binding even more strongly to IR elements than observed for the DNA binding domain of the GR.
topic androgen receptor
glucocorticoid receptor
response element
protein-DNA interaction
chimeric SPARKI protein
url https://www.frontiersin.org/article/10.3389/fmolb.2020.00004/full
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